Orchard Therapeutics’ atidarsagene autotemcel (arsa-cel, also referred to as OTL-200 and approved as Libmeldy in the European Union, UK, Iceland, Liechtenstein, and Norway), a gene-edited cell therapy intended to treat metachromatic leukodystrophy (MLD), has enabled restoration of arylsulfatase A (ARSA) enzyme activity in the peripheral blood (PB) of 4 patients treated in a compassionate use study in the United States.1 The data were presented in a poster at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.
All 4 of the patients, who were referred to by the patient IDs UMN 01 through UMN 04, showed engraftment of arsa-cel and restoration of ARSA activity in the PB. Furthermore, in all patients with sufficient follow-up, ARSA activity was restored to normal or above normal levels in PB mononuclear cells. At 1 year posttreatment, ARSA activity ranged from 60.1 to 400.8 nmol/ng/hr (mean, 225.4 nmol/ng/hr) in these patients. In the cerebrospinal fluid ARSA activity levels increased from undetectable baseline levels to a median of 0.458 nmol/ng/hr (range, 0.216 to 0.551). Hematological recovery was achieved and maintained in all 4 patients in the study.
The study also assessed patients via the Gross Motor Function Classification (GMFC)-MLD. In 3 of the 4 patients, GMFC-MLD levels were maintained. One patient, UMN 03, experienced a decrease to Level 4 on GMFC-MLD following treatment. It was noted that this patient had shown a decline in gross motor, fine motor, and cognitive function before receiving arsa-cel. Among patients for whom data was available, age-expected normal cognitive development was observed in cognitive tests.
In terms of safety, no serious adverse events (SAEs) deemed related to arsa-cel were reported. Although, UMN 03’s disease progression at 6 months after treatment was classified as an SAE. There was no indication of replication-competent lentivirus or malignancies in the 4 patients and a stable polyclonal reconstitution of hematopoiesis was inferred from integration site analysis. No antiARSA antibodies were observed in the study. Arsa-cel was deemed well-tolerated with a safety profile consistent with that of the busulfan conditioning regimentpatients underwent before treatment with the cell therapy.
READ MORE: Arsa-Cel Continues to Show Durable Benefit in MLD Outcomes Over Natural History
UMN 01 has presymptomatic early juvenile MLD and received the gene therapy at 4 years and 6 months of age, with 24 months of posttreatment follow-up. UMN 02 who has presymptomatic late infantile MLD, as treated at 7 months of age and had 24 months of follow-up. UMN 03 has early symptomatic early juvenile MLD, was treated at 7 years of age, and was followed for 18 months posttreatment. UMN 04 has early symptomatic early juvenile UMN 04 and was treated 6 years and 9 months of age. UMN 04 had only 3 months of follow-up after receiving arsa-cel. All patients were treated at the University of Minnesota.
Key Takeaways
- All 4 of the patients, who were referred to by the patient IDs UMN 01 through UMN 04, showed engraftment of arsa-cel and restoration of ARSA activity in the preipheral blood.
- In 3 of the 4 patients, GMFC-MLD levels were maintained. One patient, UMN 03, experienced a decrease to Level 4 on GMFC-MLD following treatment.
- In terms of safety, no serious adverse events (SAEs) deemed related to arsa-cel were reported. Although, UMN 03’s disease progression at 6 months after treatment was classified as an SAE.
“Patients treated while presymptomatic or in the early-symptomatic phase of MLD (able to walk independently and before the onset of cognitive decline have maintained normal motor and cognitive development,” Paul J Orchard, MD,a professor in the Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy at the University of Minnesota Medical School and colleagues wrote in the poster.1 “While longer follow-up is required, results to date are in line with those previously reported from the arsa-cel clinical development program.”
Arsa-celremains an investigational therapy in the US, with a biologics license application (BLA) currently under review by the FDA for early-onset MLD.2 The BLA was accepted by the agency with priority review in September 2023 with a Prescription Drug User Fee Act date set for March 18, 2024. In the European Union, arsa-cel is approved for an indication covering its use in patients with MLD who have biallelic mutations in the ARSA gene that have caused a decrease in ARSA enzyme activity; patients must be children with the late infantile or early juvenile forms without clinical manifestations or patients with the early juvenile form who have early clinical manifestations and retrain the ability to walk independently and have not yet shown cognitive decline.
REFERENCES
1. Orchard PJ, Gupta AO, Braun J, et al. Compassionate use of lentiviral gene therapy for metachromatic leukodystrophy. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #250
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed February 8, 2024. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
